title: Long-term intermittent hypoxia elevates cobalt levels in the brain and injures white matter in adult mice.
abstract: OBJECTIVE
  Exposure to the variable oxygenation patterns in obstructive sleep apnea (OSA) causes oxidative stress within the brain. We hypothesized that this stress is associated with increased levels of redox-active metals and white matter injury.
  
  
  METHODS
  Participants were randomly allocated to a control or experimental group (single independent variable).
  
  
  METHODS
  University animal house.
  
  
  METHODS
  Adult male C57BL/6J mice.
  
  
  METHODS
  To model OSA, mice were exposed to long-term intermittent hypoxia (LTIH) for 10 hours/day for 8 weeks or sham intermittent hypoxia (SIH).
  
  
  RESULTS
  Laser ablation-inductively coupled plasma-mass spectrometry was used to quantitatively map the distribution of the trace elements cobalt, copper, iron, and zinc in forebrain sections. Control mice contained 62 ± 7 ng cobalt/g wet weight, whereas LTIH mice contained 5600 ± 600 ng cobalt/g wet weight (P < 0.0001). Other elements were unchanged between conditions. Cobalt was concentrated within white matter regions of the brain, including the corpus callosum. Compared to that of control mice, the corpus callosum of LTIH mice had significantly more endoplasmic reticulum stress, fewer myelin-associated proteins, disorganized myelin sheaths, and more degenerated axon profiles. Because cobalt is an essential component of vitamin B12, serum methylmalonic acid (MMA) levels were measured. LTIH mice had low MMA levels (P < 0.0001), indicative of increased B12 activity.
  
  
  CONCLUSIONS
  Long-term intermittent hypoxia increases brain cobalt, predominantly in the white matter. The increased cobalt is associated with endoplasmic reticulum stress, myelin loss, and axonal injury. Low plasma methylmalonic acid levels are associated with white matter injury in long-term intermittent hypoxia and possibly in obstructive sleep apnea.
authors.affiliation: Center for Sleep and Circadian Neurobiology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Veasey
authors.forename: Jessica
authors.initials: J
authors.lastname: Lear
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Judith B
authors.initials: JB
authors.lastname: Grinspan
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Hare
authors.forename: Sihe
authors.initials: S
authors.lastname: Wang
authors.forename: Dustin
authors.initials: D
authors.lastname: Bunch
authors.forename: Philip A
authors.initials: PA
authors.lastname: Doble
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001923:Brain Chemistry / Q000502:physiology*; D003035:Cobalt / Q000032:analysis*; D004195:Disease Models, Animal; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D020181:Sleep Apnea, Obstructive / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D003035:Cobalt
keywords: Brain; ER stress; cobalt; copper; corpus callosum; homocysteine; iron; methylmalonic acid; myelin; obstructive sleep apnea; oxidative stress; zinc